1. Technical Field
This document relates to materials and methods for treating subjects having a disease associated with Human Epidermal Growth Factor Receptor-3 (HER-3) by administering a first agent that binds to HER-3, in combination with a second agent that binds or inhibits another Human Epidermal Growth Factor Receptor (HER) family member. The first and the second agent may be any kind of molecule that binds to HER-3 or binds to and/or inhibits another HER family member, respectively, including, but not limited to a biological compound, such as an antigen binding protein, a small molecular tyrosine kinase inhibitor, an siRNA, or a natural substance.
2. Background
HER-3, also known as ErbB3, is a receptor protein tyrosine kinase that belongs to the epidermal growth factor receptor (EGF-R, also known as HER) family of receptor protein tyrosine kinases, which also includes HER-1 (also known as EGF-R or erbB), HER-2 (also known as erbB2), and HER-4 (also known as erbB4) (Plowman et al. (1990) Proc. Natl. Acad. Sci. US 87:4905-4909; Kraus et al. (1989) Proc. Natl. Acad. Sci. US 86:9193-9197; and Kraus et al. (1993) Proc. Natl. Acad. Sci. US 90:2900-2904). Like the prototypical epidermal growth factor receptor, the transmembrane receptor HER-3 consists of an extracellular ligand-binding domain (ECD), a dimerization domain within the ECD, a transmembrane domain (TMD), an intracellular protein tyrosine kinase domain (TKD), and a C-terminal phosphorylation domain.
The ligand for HER-3, known as heregulin (HRG), binds to the extracellular domain of HER-3 and activates receptor-mediated signaling by promoting dimerization with other human epidermal growth factor receptor (HER) family members, subsequent transphosphorylation of the intracellular HER-3 domain, and activation of downstream signaling cascades. Dimer formation with multiple HER family members expand the signaling potential of HER-3, and is a means for signal diversification as well as signal amplification.